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Adrenergic receptors are prominent targets for this approach because they are prototypical G protein\u2010coupled receptors with high clinical relevance in bronchial and cardiovascular diseases. Here, we employed the azobenzene\u2010based compound photoazolol\u20101 in combination with time\u2010resolved serial crystallography at X\u2010ray free\u2010electron lasers to resolve the molecular mechanisms by which photoswitchable \u03b2\u2010blockers modulate activity of the \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    \u2010adrenoceptor (\u03b2\n                    <jats:sub>2<\/jats:sub>\n                    AR). Time\u2010resolved structures of the receptor bound to\n                    <jats:italic>trans<\/jats:italic>\n                    \u2010photoazolol\u20101 (pre\u2010photoconversion), a strained intermediate in the nanosecond range, and the fully photoisomerized\n                    <jats:italic>cis<\/jats:italic>\n                    \u2010photoazolol\u20101 reveal how isomerization of the azobenzene moiety induces distinct conformational changes within the orthosteric ligand binding pocket. Within seconds, light\u2010excited photoazolol\u20101 adopts a new binding pose, altering interactions with extracellular loop 2 and shifting the positions of transmembrane helices 5, 6, and 7. Functional assays of \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    AR in cellular membranes show that photoazolol\u20101 acts as an efficacy photoswitch, changing from an inverse agonist to a neutral antagonist upon isomerization without leaving the binding pocket. In combination, these findings suggest a molecular mechanism for activity modulation via efficacy photoswitches and provide a framework for designing ligands that exploit light\u2010driven transitions within the binding pocket to achieve spatiotemporal control of receptor function.\n                  <\/jats:p>","DOI":"10.1002\/anie.202517995","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T14:16:06Z","timestamp":1773843366000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Structural Mechanism of an Efficacy Photoswitch Targeting the \u03b2\n                    <sub>2<\/sub>\n                    \u2010adrenergic Receptor"],"prefix":"10.1002","volume":"65","author":[{"given":"Robin","family":"Stipp","sequence":"first","affiliation":[{"name":"PSI Center for Life Sciences, Paul Scherrer Institute  Villigen 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